Safeguarding American Agriculture

Federal Relay Service

APHIS is an agency of USDA’s Marketing and Regulatory Programs (Voice/TTY/ASCII/Spanish)

 An Equal Opportunity Provider and Employer 1-800-877-8339

 

 

September 19, 2007 

VETERINARY SERVICES MEMORANDUM NO. 800.111 

TO: VS Management Team 

 Directors, Center for Veterinary Biologics 

 Biologics Licensees, Permittees, and Applicants 

FROM: John R. Clifford /s/ John R. Clifford 

 Deputy Administrator 

SUBJECT: Viral Strain Changes in Equine Influenza and Swine Influenza Vaccines 

 (Killed Virus) 

I. PURPOSE 

This memorandum gives guidance to licensees, permittees, and applicants, per Title 9, 

Code of Federal Regulations (9CFR) 102.5(c)(1), concerning expedited procedures for 

influenza virus strain changes in licensed or permitted products containing inactivated 

(killed) equine and swine influenza viruses. 

II. BACKGROUND 

Equine influenza and swine influenza are highly contagious diseases that can have a 

significant economic impact to livestock owners. Equine and swine influenza viruses 

tended to remain stable in the environment for many years. Recently, however, antigenic 

shift and drift have been increasingly evident in viruses isolated from field cases of 

influenza. There is evidence from field studies that older influenza vaccines do not 

adequately protect animals from the currently circulating viruses. Expedited regulatory 

procedures that do not compromise the demonstrated efficacy and safety of the licensed 

products are necessary to keep pace with the antigenic changes seen in the field. 

III. POLICY 

The Center for Veterinary Biologics will, under the conditions described below, consider 

changes to the Master Seeds in licensed and permitted killed equine influenza and swine 

influenza vaccines without requiring additional full-scale efficacy and field safety 

studies, provided that the production methods have not been significantly altered. 

 A. General guidelines 

 1. H7N7 (subtype A1) equine influenza strains are no longer considered 

United States 

Department of 

Agriculture

Animal and Plant 

Health Inspection 

Service 

Washington, DC 

20250 
VETERINARY SERVICES MEMORANDUM NO. 800.111 

Page 2 

 relevant to protection against currently circulating field strains. H7N7 

 equine influenza virus strains may be removed from currently licensed 

 products without prejudice, and firms are encouraged to remove them. 

 2. Proposals for additions or substitutions of new strains, or deletions of 

 already present strains, must be submitted to CVB for review and approval 

 prior to changing the licensed products. 

 Equine influenza strains should be those recommended by the OIE Expert 

 Surveillance Panel on EIV or otherwise justified by peer-reviewed scientific 

 literature. Strains other than those specifically recommended by the OIE 

 Panel may be used, provided that an equivalent relationship to the 

 recommended strain is demonstrated by subtyping, sequencing, and 

 antigenic analysis using hemagglutination inhibition (HI) tests, in a manner 

 acceptable to the CVB. 

 Swine influenza strains should be those justified by expert evaluation or 

 peer-reviewed scientific literature and subtyping, sequencing, and antigenic 

 analysis using HI tests, in a manner acceptable to the CVB. 

 3. A licensed product may not contain more than three strains of a 

 subtype. 

 B. Substitution of strains within currently licensed products 

 1. Up to two strain substitutions within each of the subtypes present in the 

 currently licensed product may be made at any one time. The antigen 

 concentration per dose of each substitute must not be less than the minimum 

 concentration specified in the currently approved Outline of Production for 

 the strain being replaced, unless efficacy of the lowered antigen 

 concentration per dose is demonstrated by a host animal challenge study 

 acceptable to the CVB. 

 2. Firms must demonstrate the immunogenicity of new strains by 

 demonstrating that the revised product formulation generates a similar 

 immune response as the original formulation in host animals or a suitable 

 laboratory animal model. 

 a. The newly formulated product should be tested in at least six 

 immunologically naive host animals at the minimum age recommended 

 for vaccination. Animals that demonstrate an anamnestic response are 

 removed from the study, but may be replaced with an equal number of 

 new animals in a secondary study. Following completion of the study, 

 the antibody geometric mean titer (GMT) should not be less than that 

 demonstrated in the original efficacy study when compared at the same 
VETERINARY SERVICES MEMORANDUM NO. 800.111 

Page 3 

 post-vaccination interval using the same validated assay, but with the 

 new strain’s antigen and not the original antigen. 

 b. The newly formulated product may be tested in a laboratory animal 

 model acceptable to the CVB, provided at least 10 animals are 

 vaccinated. The antibody GMT should not be less than that achieved in 

 the original efficacy study when compared at the same post-vaccination 

 interval using the same validated assay. 

 c. The use of frozen archived serum samples in an assay directly 

 comparing serologic response to old and new strains will require specific 

 approval by the CVB. 

 d. When substituting new influenza strains in combination products 

 containing other agents, where antigen interference studies have already 

 been completed satisfactorily, it is not necessary to conduct further 

 interference studies. 

 C. Addition of strains belonging to subtypes already present 

 1. Based on adequate justification, additional strains of each subtype may be 

 added to a licensed product. 

 For swine influenza vaccines, reassortants arising from new combinations of 

 existing hemagglutinin (H) and neurominidase (N) gene segments (e.g., 

 reassortment of H1N1 and H3N2 subtypes into a H1N2 subtype) will not be 

 considered “new” subtypes. The guidelines in this section apply to the 

 addition of such new reassortants. 

 2. The antigenic content per dose of the original strains must not be decreased 

 upon the addition of additional strains, unless efficacy of the lowered 

 antigen concentration per dose is demonstrated by a host animal challenge 

 study acceptable to the CVB. 

 3. Testing requirements to support such additions are the same as those 

 described in Section III.B.2. 

 D. Addition of strains belonging to new subtypes 

 1. Based on adequate justification, strains of new subtypes may be added to a 

 licensed product. 

 2. The minimum antigen content per dose of each of the existing strains must 

 not be decreased upon the addition of a new subtype, unless efficacy of the 

 lowered antigen concentration per dose is demonstrated by a host animal 

 challenge study acceptable to the CVB. 
VETERINARY SERVICES MEMORANDUM NO. 800.111 

Page 4 

 3. The immunogenicity of a strain of the new subtype must be demonstrated by 

 host animal vaccination/challenge, using at least 10 vaccinates and 5 

 controls. The challenge virus must be a field-relevant strain. 

 An entirely new equine or swine influenza vaccine manufactured according 

 to a new process will require efficacy and field safety data as for any new 

 product. Where a reasonable expectation of efficacy can be demonstrated, a 

 firm may apply for a conditional license to expedite use of the product in the 

 field, as described in 9 CFR 102.6 and Veterinary Services Memorandum 

 No. 800.75. Until testing for full licensure of this new product is completed, 

 restrictions on the conditionally licensed vaccine will apply. 

IV. MASTER SEED VIRUS REQUIREMENTS 

All applicable Standard Requirements for Master Seeds, specified in 9CFR section 113.200 

apply. Additionally, the Master Seed characterization must include the H and N subtype 

designations. Sequence data, indicating the immunologically critical regions in the viral genome 

(e.g. the nucleotide sequence of the H gene), should be submitted on electronic disk. 

V. PRODUCTION RECOMMENDATIONS 

Firms are encouraged to develop the Single Radial Diffusion (SRD) assay as a measurement of 

H antigenic content during production.1, 2 The SRD test is not suitable in the presence of 

adjuvant but is a reliable method for standardization of vaccine content prior to adding adjuvant. 

Reagents specific for the OIE recommended EIV vaccine strains are available from the National 

Institute for Biological Standards and Control, Hertfordshire, United Kingdom. 

Equine antisera specific for various EIV vaccine strains are available as European 

Pharmacopoeia Biological Reference Preparations (EP BRPs) for serologic testing of EIV 

vaccines. They are available at the European Directorate for the Quality of Medicines, Cedex, 

France. 

Currently, SRD reagents specific for SIV vaccine strains are not available. An alternative 

antigen quantification test acceptable to the CVB may be used. 

VI. LABELING 

Subtype and strain designations, specified according to accepted standards of influenza virus 

nomenclature, are to be included on the labeling for the product. 

VII. REFERENCES 

1. Williams MS. Single-radial-immunodiffusion as an in vitro potency assay for 

 human inactivated viral vaccines. Vet Microbiol 37:253-262, 1993. 
VETERINARY SERVICES MEMORANDUM NO. 800.111 

Page 5 

2. Wood JM, Schild GC, Newman RW, Seagroatt V. An improved single-radial- 

 immunodiffusion technique for the assay of influenza haemagglutinin antigen: 

 application for potency determinations of inactivated whole virus and subunit 

 vaccines. J Biol Stand 5:237-247, 1977.